Synthesis of 4-phosphonomethyl-DL-phenylalanine (Formula 1a), and derivatives thereof (Formulas 1b-d) have previously been reported .sup.1-4 (See Table 1). The purposes of such preparations were to utilize the prepared 4-phosphonomethyl-DL-phenylalanines as competitive antagonists of N-methyl-D-aspartic acid .sup.2 or as mimics of O-phosphotyrosine .sup.1,3,4. These previously prepared derivatives are not suitable for facile incorporation into peptides or peptide mimetics using standard protocols developed for either solution-phase or solid-phase peptide synthesis using "Fmoc protocols" .sup.5,6.
Central to peptide synthesis is the protection of reactive functional groups with moieties which are easily removed under conditions which are compatible with the preservation of other functionalities in the peptide. A major branch of peptide chemistry has recently evolved using 9-fluorenylmethyloxycarbonyl (Fmoc) groups for protection of .alpha.-amino groups during coupling reactions of amino acid monomers into peptide chains. The Fmoc groups are then generally removed by brief treatment with an appropriate base such as piperidine. In such reactions, other chemically reactive groups on the amino acid monomers must be protected by functionalities which are stable to the basic conditions utilized to remove Fmoc groups. Traditionally, these other groups were removed by mild acid treatment (e.g., trifluoroacetic acid) such as used to cleave the finished peptide from a given resin. The tert-butyl group is used widely in Fmoc-bearing residues for the protection of hydroxyl groups, since it is stable to base and easily removed by mild acid treatment. Unlike the present inventive compounds, the prior known 4-phosphonomethyl-DL-phenyl-alanine compounds shown in Table 1 (Compounds 1a-1d) require significant synthetic manipulation to render them suitable for peptide synthesis.
Previously, non-benzylic .alpha.-fluorophosphonates have been converted to .alpha.,.alpha.-difluorophosphonates using electrophilic fluorinating reagents.sup.1, and benzylic .alpha.-fluorophosphonates have been prepared from .alpha.-hydroxyphosphonates using (diethylamino)sulfur trifluoride (DAST).sup.10. The conversion of .alpha.-oxoarylacetates to .alpha.,.alpha.-difluoroarylacetates using DAST.sup.11 has also been reported.
TABLE 1 ______________________________________ ##STR1## R.sup.1 R.sup.2 R.sup.3 Ref ______________________________________ 1a H H OH 1,2,3,4 1b Et Bz.sup.a OH 1 1c Et Ac OMe 2 1d H H HNBn.sup.b 4 ______________________________________ .sup.a Bz = benzoyl .sup.b Bn = benzyl